-Marcie Zinn, PhD, neuropsychologist and research consultant at Stanford University
Friday, October 24, 2014
-Marcie Zinn, PhD, neuropsychologist and research consultant at Stanford University
Monday, October 20, 2014
Immune system disruption
The search for answers
By Kris Newby
Illustration by Jeffrey Decoster
Photography by Timothy Archibald
Erin keeps a photo of herself playing soccer in the living room of her
tidy cottage near San Francisco Bay. It captures her image frozen in
time and space, hurtling like a comet between two opponents, her
white-blond ponytail fanned out like flames.
video interview- https://www.youtube.com/watch?v=pvtbsStLQWk
Related reading: The Institute for Immunity, Transplantation and Infection
Related reading: Hacking the immune system: The hunt for chronic
"She was a midfielder with boundless energy, lightning fast," recalls
the coach of her Big Ten college soccer team.
Erin, in her early 30s, always assumed that soccer would be at the
center of her life. As a little girl, her favorite toy was a soccer
ball, a present from a cousin living in Rome. At age 4, she drew a
picture of herself competing in the Olympics. In high school, she was
invited to try out for the national team's talent pool. After college,
she played for the Detroit Jaguars, a semi-professional team.
But her dream of playing competitive soccer abruptly ended after a
trip to Mexico in 2007.
"I was doing social work at an orphanage when I got sick," says Erin
(who asked that her real name not be used). "I passed out and was
hospitalized with a high fever, low blood pressure and swollen lymph
nodes. After that, I was never the same."
Thus began her seven-year journey battling a devastating illness with
no known cause or cure. She was bedridden for all but four hours a
day. She could stand only for 20 minutes without fainting. But the
worst symptom was the brain fog.
"It was like my thoughts were stuck in molasses," says Erin.
No one could figure out what was wrong or how to fix it. She was
labeled with chronic fatigue syndrome. Despair set in as the door to
her old life slowly closed.
Interrogating the immune system
That same year a door opened on the other end of San Francisco Bay, in
a windowless basement of a clinical research building at Stanford
University. Here Mark Davis, PhD, an immunologist with a computer
hacker's mindset, was launching a center that aimed to break open the
black box called the human immune system. This dynamic network of
biological sensors, cells, secretions and genes is like a sixth sense,
able to detect microbial friend from foe in the food we eat, the
things we touch and the air we breathe. The most intelligent facets of
the immune system are still a mystery. How does it differentiate
between the cells that are part of you and the interlopers? What are
the steps involved in launching an army of white blood cells to attack
a microbial invader? How does the system dial down the resulting
tissue-damaging inflammation? How do our traitorous cells — the
cancers — make themselves invisible to our immune system?
Davis, director of Stanford's Institute for Immunology,
Transplantation and Infection, is in the right place at the right time
for this quest, swimming in the primordial soup of creative
disruption, Silicon Valley. At long Stanford cafeteria tables
frequented by geneticists, bioengineers, math geniuses, computer
programmers, surgeons and cancer biologists, ideas just happen. And
sometimes, visionary entrepreneurs throw money at these ideas. Such is
the case with Davis' Human Immune Monitoring Center, which before long
had enough funding to acquire a CyTOF, a time-of-flight mass
spectrometer for high-speed acquisition of multiparametric single-cell
data. (If someone asks you if you want one of these instruments, just
The CyTOF enables researchers to detect 40 different components within
a single cell at the rate of 1,000 cells per second. It not only
measures static levels of proteins, useful in identifying different
types of immune cells, but it also detects minute changes in signaling
proteins within cells in response to various stimuli. Using this
device, a staggering amount of data is generated. And armed with
big-data analytical methods developed during the Human Genome Project,
Davis' multidisciplinary team is trying to bring order and meaning to
When it's all done, the team hopes to create a map of what a healthy
person's immune system should look like and a flow chart depicting how
immune-system signaling pathways work.
The ultimate goal of Davis' "Human Immunome Project" is to develop
better tools to answer immunological questions no one can answer now.
One of the first: What is wrong with the immune systems of patients
like Erin, and how can we help them get better?
Two years into her illness, Erin was broken. On any given day, she
would cycle through a laundry list of symptoms: brain fog, dizziness,
light sensitivity, a sore throat, nausea, swollen lymph nodes,
crushing fatigue, a racing heart, ear ringing, drenching sweats and
During this time, she had lost some of her most active and athletic
friends, who grew impatient with the waxing and waning symptoms that
prevented her from the leaving the house on most days.
"I had times where I'd shut the blinds, lie down and hope for a better
day," says Erin. "Literally, my escape was through my dreams. I just
couldn't stand to be in my body."
Her life revolved around doctors' appointments. One physician ruled
out infectious diseases. Neurologists examined her for seizure
disorders and brain tumors. A rheumatologist evaluated her for
systemic lupus erythematosus and other inflammatory diseases. An
endocrinologist agreed that the origin of her fatigue was not the
thyroid, the adrenals or any other gland. A cardiologist assured her
it was not her heart.
None of them could settle on a definitive diagnosis, so the physicians
tagged her with the insurance code for chronic fatigue syndrome, a
controversial diagnosis for a set of symptoms also sometimes labeled
as CFIDS — for chronic fatigue and immune dysfunction syndrome — and
ME — for myalgic encephalomyelitis. The dominant moniker today is
No one knows what causes ME/CFS. Some think that an infectious agent
or overactive immune system triggers it. Others blame genetic flaws,
environmental factors or a combination of any of the above.
Roughly 17 million people worldwide (1 million to 4 million in the
United States) have ME/CFS. It strikes people of all ages and racial,
ethnic and socioeconomic groups. It is diagnosed two to four times
more often in women than men.
It's a syndrome that gets little respect in the medical community
because, with no tangible cause and an ever-changing constellation of
symptoms, patients often get labeled as hypochondriacs, malingerers or
seekers of addictive pain medications. The primary diagnostic
criterion for this condition is infuriatingly vague — "six or more
consecutive months of severe fatigue" — virtually unchanged since
As Erin went from specialist to specialist, well-meaning doctors grew
frustrated with their inability to help her. One day Erin blacked out
while driving, almost hitting a streetlight. After another fainting
accident, an emergency room physician told her, "On hot days, women
"I felt objectified, like a slab of meat," says Erin.
Finally, in 2009 Erin was diagnosed with postural orthostatic
tachycardia syndrome — which accounted for her fainting spells. For
treatment, her cardiologist sent her to Stanford Hospital's cardiology
clinic to see one of the nation's few POTS specialists, cardiac
electrophysiologist Karen Friday, MD.
POTS, which often accompanies ME/CFS, is a fainting disorder
associated with an abnormal increase in heart rate and low blood
pressure. The mechanism is unknown, but some people develop it after
contracting viral or bacterial infections like mononucleosis,
pneumonia or Lyme disease. Friday prescribed fludrocortisone to manage
Erin's low blood pressure, but to explore the possibility of an
underlying microbial trigger, she sent Erin to see Stanford professor
of infectious diseases José Montoya, MD.
Montoya, 54, dapper in his white coat and tie and smiling widely,
greeted Erin with a bear hug and told her in his thick Colombian
accent, "I want to make your life beautiful again."
"Dr. Montoya was a shining beacon of hope," says Erin.
Montoya's ethos to reduce patient suffering was shaped by a
hardworking, single mother and the iron-fisted priests at his Catholic
school in Cali, Colombia. He was accepted into medical school at age
18, after receiving the third-highest qualifying exam score in his
native country that year. After medical school he went on to Tulane
University School of Medicine for his residency, then joined the
infectious disease division at Stanford. At Stanford he became a
world-recognized authority on infections affecting heart transplant
recipients and on toxoplasmosis, a common parasitic disease.
Montoya conducted a detailed medical history and physical exam on
Erin, then ordered a battery of tests for viruses, bacteria and fungi.
His wide-net diagnostic approach paid off; he found two blood-borne
microbes — Human Herpesvirus-4 and the coxsackie virus — known to
cause chronic disease and POTS.
Though Montoya wasn't sure if these viruses were at the root of Erin's
illness or merely collateral infections, he started her on a high dose
of the antiviral drug famciclovir. Erin was relieved to finally have a
physician who wasn't going to punt her case to another specialist.
"I wanted to live my life again," says Erin.
Montoya is one of only a handful of clinician-researchers who accept
ME/CFS patients, and he currently has a waiting list of about 150.
Back in 2005, while attending a conference on toxoplasmosis in Paris,
Montoya told his mentor that he wanted to research ME/CFS. His mentor
scoffed at the idea, pointing to a homeless person lying in a Parisian
"That's going to be you if you go into chronic fatigue research," the
mentor told him.
The hard truth is that most medical research labs rely in large part
on U.S. government funding, and the ME/CFS research budget is
insufficient to support a typical university research lab.
The National Institutes of Health, the largest funder of medical
research in the United States, allocated only $5 million for ME/CFS
research in 2013. (To put this in context, the annual NIH research
budget for multiple sclerosis, with 400,000 sufferers, is $112
million.) The reasons behind this underfunding are complicated.
One factor is that the NIH funding process favors well-defined
diseases that fit neatly into medical specialties like cardiology,
cancer and neurology. Most of these medical societies have organized
lobbying efforts, sometimes backed by pharmaceutical or medical
technology companies. Another factor is that collectively ME/CFS
patients are too sick to organize, raise money and lobby for research
dollars. And then there is the stigma associated with the condition;
some NIH grant reviewers are reluctant to fund research because they
believe that ME/CFS is a psychosomatic, "all in the head," disorder.
(To remedy this, the NIH recently created a special emphasis panel so
that researchers familiar with the condition review grant
But none of this deterred Montoya, who was driven to do something for
the suffering patients queuing up for appointments.
Opportunity knocked in 2008 when a wealthy donor met with Montoya to
talk about the ME/CFS problem. He asked if a $5 million donation for
research could make a difference.
Montoya could hardly believe the sum, replying, "Yes, give me five years."
With the freedom of private funding, Montoya was able to take a
multifaceted and rigorous approach to analyzing ME/CFS. Traditionally,
NIH funding is awarded through medical specialty groups that tend to
favor research that tests one narrow hypothesis about a disease. For
example, a researcher might get funded to screen blood samples for one
virus, or treat patients with one drug. This approach takes a long
time, and researchers typically aren't able to share and build on
discoveries for years.
Montoya's game plan was to use a big-picture, big-data strategy to
find out what was wrong with patients like Erin. His first step in
launching the Stanford Initiative on Infection-Associated Chronic
Diseases was to convince a dozen or so academic investigators to
venture out of their comfort zones to research a wildly unpopular
disease using technologies yet to be developed.
Montoya convinced experts in immunology, rheumatology, genetics,
bioengineering, anesthesiology, neuroradiology, cardiology,
psychiatry, infectious diseases and bioinformatics to all work
together. The team members would be searching blood samples for
infectious microbes, inflammation-related molecules and genetic flaws.
They'd do brain scans and physical exams. They'd survey study subjects
for fatigue levels and medical histories. Then they'd compare all this
data with that of healthy people to see what was different. Next, he
launched a Bay Area recruitment campaign for 200 patients who met the
Centers for Disease Control's definition for chronic fatigue syndrome,
including Erin, and 400 age- and sex-matched healthy volunteers, all
of whom agreed to donate eight tubes of blood and be poked, scanned
and surveyed over the next decade.
The most complex part of the ME/CFS initiative was the exploration
into what was happening with the immune system of these patients. For
this role, he needed an expert who didn't care about the ME/CFS stigma
or how things have been done in the past. So he called on Mark Davis.
There will be blood
Davis, in well-worn jeans and running shoes, leans back in his chair,
surrounded by pillar-piles of scientific papers. At first glance one
might assume that he is — in California-speak — a mellow dude.
But looks can be deceiving, because Davis, who discovered how T cells
help a body fight off infections, is all about the fight. [See story,
As if to prove this point, Davis reaches into a random stack of paper
and pulls out a black-and-white photo of a collegiate fencing match.
"This is me," he says, pointing to a man in white flying off the
ground, plunging the tip of a silver foil directly between the eyes of
a masked opponent. "I like to poke people."
He then reaches into another stack of paper and pulls out the Dec. 19,
2008, issue of Immunity. It is a poke-in-the-eye to fellow
immunologists, an essay titled, "A Prescription for Human Immunology."
In this oft-quoted paper, he describes immunology as a field known for
its "impenetrable jargon, byzantine complexity and acrimonious
He also chides many of his colleagues for spending too much time on
mouse studies and not enough on human studies. For immunological
studies, mice are fast and easy. They can be bred with specific
diseases, such as diabetes or Parkinson's, and then dissected to
evaluate the effectiveness of experimental treatments. There are
relatively few regulatory, financial and ethical hurdles to working
with mice. He emphasizes that lab mice live in isolated, disease-free,
temperature-controlled environments, far different from the crowded,
germ-ridden urban habitats of your typical Homo sapiens. (Most humans
are infected with six different herpes viruses, and who knows what
else.) The other problem with "mouse models" is that their common
ancestors are genetically separated from Homo sapiens by some 65
"Inbred mice have not, in most cases, been a reliable guide for
developing treatments for human immunological diseases," says Davis.
Instead, he would like to shift the focus of immunology research back
to where it can do the most good — to humans and their blood. And
along the way, he'd like to slay a few sacred cows of medicine.
First off, Davis believes it's time to rethink the CBC or complete
blood count, the most commonly ordered medical test on the planet. The
CBC, which has changed little since it was put into mainstream use in
the '50s, provides physicians with relative numbers of a patient's
red, white and platelet blood cells. This test isn't really "complete"
and it doesn't begin to capture the nuances of a working immune
As researchers gain a better understanding of this system, he'd like
to develop a new set of metrics for immune system health that
communicates more of a continuum of health rather than a
black-and-white declaration. If the immune system is underactive, a
person is open to infections, mutations and premature aging. If it is
overactive, a person may suffer from allergies, autoimmune disease and
excessive inflammation. Davis wants to redefine health as an immune
system in balance, then develop better reporting tools to help
clinicians determine if a patient is fighting a virus, a bacteria, an
allergy or environmental toxins.
Davis' field of dreams for this effort is Stanford's Human Immune
Monitoring Center. Launched in 2007, today the center consists of
dozens of instruments that provide standardized, state-of-the-art
immune system analysis at the RNA, protein and cellular levels. Its
gene-sequencing instrumentation is located in a nearby building and
shared with the Stanford Functional Genomics Facility. For researchers
both inside and outside of the university, the center's 15-person
staff provides a one-stop shop for these services. At the start of a
project, the center's director, Holden Maecker, PhD, meets with
investigators to help plan studies and determine needs, such as what
samples to take, how to store those samples and which tests will best
answer their scientific questions. There is also assistance on results
archiving, reporting and data mining.
"We have about 60 different projects under way at the center right
now," says Maecker. These include searches for immune biomarkers for
aging, Alzheimer's, autoimmune disease, cancer, chronic pain,
rejection in organ transplantation and viral infections.
"I believe this is the only facility of its kind anywhere," says Davis.
Montoya's chronic illness initiative is the largest project in the
HIMC at this time, and the complexity of the task ahead is daunting.
The staff is looking for meaningful patterns in the many components of
the 600 blood samples, including dozens of cytokines, 35 cell-surface
proteins, 15 or so types of blood cells, and more than 47,000 genes
and regulatory nucleic acids. The challenge is not only to quantify
the normal ranges for these components, but also to understand
relationships between the components and reverse-engineer the cascade
of biochemical reactions that drive immune system processes. He
anticipates it will take about a year to run all 600 samples through
"It's like dumping a hundred different puzzles on the floor and trying
to find two pieces that fit," says Davis.
The workhorses for these tasks are the center's two CyTOFs. Stanford
has seven of these $630,000 instruments, more than any other academic
medical center, thanks to Garry Nolan, PhD, a Stanford professor of
microbiology and immunology. Nolan purchased the first commercially
available CyTOF, and as an early adopter developed protocols for using
it in cancer biology, immunology and cell biology. He now holds equity
in Fluidigm, a company that manufactures the machines.
His enthusiasm for the technology and his willingness to share what
he's learned has catalyzed an active Stanford community of CyTOF
"With seven CyTOFs on campus, Stanford continues to innovate and lead
the way in 'deep-profiling' studies of the immune system," says Nolan
Through this work, the Stanford team hopes to gain a better
understanding of the complex, inner workings of the immune system.
This will ultimately give physicians and their patients the tools to
answer the fundamental question, "How is my immune system doing
Putting the pieces together
This past March, four years after the launch of the ME/CFS initiative,
Montoya held an all-day symposium to present early findings on what's
happening within the hearts, blood, brains and genomes of ME/CFS
patients. The lecture hall was packed with researchers from Australia,
Canada, the United Kingdom and the United States, as well as patients,
all eager for any news on a research agenda that had been stalled for
(These presentations can be watched at
At the end of the day, the biggest news was the identification of a
number of biological markers that indicate ME/CFS patients may be
suffering from out-of-control inflammation.
First up was a neuroinflammation researcher, Jarred Younger, PhD, who
worked with the HIMC to measure daily fluctuations of 74 blood markers
and cytokines. For this study, published in the Journal of
gave blood once a day for 25 days, and reported their fatigue levels
on a hand-held computer twice a day. (Younger moved to the University
of Alabama in Birmingham in August.) Through complex statistical
analysis, the team found 12 cytokines that were consistently elevated
on days that ME/CFS patients felt the most fatigued. One of these
cytokines, leptin, activates microglial cells, the brain's first line
of defense against infections. When microglial cells are primed, they
start pumping out signaling chemicals that generate the flulike
symptoms commonly reported by ME/CFS patients — fatigue, headaches and
Amit Kaushal, a medical resident with a PhD in bioinformatics, did the
first pass on genomic analysis. For his part of the investigation, he
scanned the blood of 200 ME/CFS patients and 400 healthy subjects for
47,000 gene elements, then ran this data through the Nextbio Disease
Atlas, a publically accessible database that catalogs gene markers
associated with specific diseases. After analysis, he found genetic
markers in the blood of ME/CFS patients similar to those in patients
with well-defined chronic inflammatory diseases.
The quarterback for the search for infectious microbes is W. Ian
Lipkin, MD, a renowned microbe hunter and the director of the Center
for Infection and Immunity at Columbia University's Mailman School of
Public Health. He is using high-throughput sequencing platforms that
enable rapid identification and molecular characterization of known
and novel disease agents.
"We decided to go in without any preconceived notions about what we'd
find," says Lipkin. "Our approach is comprehensive, rigorous and quite
In the first analysis, his team found no significant differences in
the types of infectious organisms present in the blood of people with
ME/CFS or their matched normal controls. In the next phase he'll
search inside the blood cells and analyze the gastrointestinal
microbiome for the presence of bacteria or viruses that may trigger
the immunological disturbances that are so disabling in ME/CFS. The
objective of this work is to identify the agents responsible for
initiating and perpetuating disease. This could lead to vaccines,
drugs or probiotic interventions.
While not all of these results have been published or independently
confirmed, the researchers were excited about finding measurable,
physical differences between ME/CFS patients and healthy controls.
(Stanford assistant professor of radiology Michael Zeineh, MD, has
identified structural brain abnormalities in the ME/CFS patients —
findings are slated for publication in the coming months.) More pieces
of the puzzle are coming together, providing other ME/CFS researchers
with ideas to build on. For ME/CFS patients it was validation — their
symptoms are real, with measurable biological markers.
Eight months after seeing Montoya, Erin's recovery from ME/CFS started
with fleeting windows of cognitive clarity. She was on high-dose
antivirals and POTS medications for about five years, and her recovery
was infuriatingly slow and inconsistent. It was like wiping off a
mirror in a steamy bathroom. She saw her former self briefly, then the
image fogged over again.
Montoya doesn't know why these drugs worked for Erin, but he knew from
treating other patients that beating back viral infections sometimes
helps get an immune system back into balance.
Erin also believes that the antiviral and POTS drugs were instrumental
in her recovery, but other factors — family support, meditation and
Montoya's coaching — were also important.
One of Montoya's key messages to ME/CFS patients is this: If you have
one good day, don't try to make up for lost time by overexerting
"Don't burn out your engine," says Montoya, because the resulting
crash can reset the recovery process by months.
And at appointments he would remind Erin, "Take in all the love that
is all around you and use it to heal."
During her illness, Erin's mother became her advocate, managing her
medical issues and driving her to appointments. Her father added her
to his health insurance policy so she could afford the visits to
medical specialists. And her sister, who is her best friend and
housemate, was her wingman.
"My sister was my voice of hope," says Erin. "She'd tell me, 'OK, you
took five steps forward and two back today, but maybe tomorrow you'll
take six steps forward and only one back.'"
It's been seven years since Erin fell into the abyss of a mysterious
illness. This girl interrupted, now a woman, is picking up the pieces
of her life and starting to live again.
Today, she works as a social worker and therapist. She plays soccer in
a local league. She's also started dating again. It gives her hope
that researchers are finally focused on ME/CFS and that others may be
able to benefit from the treatment that has given her life back.
As she packs for a camping trip, she reflects on how this illness has
"It's made me a person of more depth and compassion," says Erin.
"Before, I'd been so active, I didn't have the opportunity to sit with
myself in this way and take a deeper inward journey. Adventure had
been the focus of my life. As I sit with clients who are coming in
with devastating situations, with unknown futures, I'm able to share
with them hope and the power of self-fulfilling prophesies. I help
them find those things inside, spiritually, that will help them meet
the adversities in their lives."
At this point her voice becomes soft, almost a whisper, as she says,
"I'll always miss playing soccer at a competitive level, but I've
gained so much. It's helped me reinterpret what success looks like.
It's not everything you achieve and how many games you win. It's the
process of getting there. This is my biggest achievement — recovering
from this illness."
In soccer, a "hat trick" is where a player scores three goals in a
row. Montoya achieved his first goal, the launch of the first major
ME/CFS research initiative, with a little funding luck and the
recruitment of a top-notch research team. With the assistance of Davis
and his immune system hackers, he's close to reaching his second goal:
the identification of biomarkers and causes, which will enable
physicians to provide a definitive diagnosis and treatment options to
patients suffering from this debilitating condition.
The third goal of his hoped-for hat trick will be a whole new way to
look at the human immune system. It's a game changer. It will provide
researchers with a new playbook of research strategies to help them
discover the causes of other confounding conditions, from Lyme disease
to multiple sclerosis to fibromyalgia. It will provide clinicians with
a better set of metrics for assessing patients' health. And then the
patients lying in dark rooms with forgotten diseases, whose numbers
could fill hundreds of soccer stadiums, will have reasons to stand up
Kris Newby is the communications manager for Spectrum, the Stanford
Center for Clinical and Translational Research and Education. Email
her at email@example.com.
Email the author- firstname.lastname@example.org , email@example.com
Sunday, October 12, 2014
Tuesday, October 7, 2014
Friday, October 3, 2014
Cytokines patterns supported both Th1 and Th2 cytokine profiles in CFS and MS. Similarities in the cytokine profiles of MS and CFS, combined with the already acknowledged similarities in immune cell function and symptoms, suggests a neuroimmune pathology for CFS with parallels to that of MS.
* * *
Why, when my disability comes up in conversation with someone new, I start with the comment "I have something very similar to MS" -- they really are very similar and MS is something they can get their heads around. Many times, the conversation ends there.
If they ask for more information, level 2 is "a neurological disease combined with poor immune function." Again, many times this is all the information necessary.
If they continue to probe, "CFS, which is known in the rest of the world as Myalgic Encephalomyelitis", and a brief explanation of WHY the US insists on calling it CFS.
Thursday, October 2, 2014
Hi, my name is Deborah Brooks. I also suffer from chronic fatigue syndrome. I am currently completing a Master of Clinical Psychology degree at Cairnmillar Institute in Australia, and my supervisor for this research project is Dr Alistair Anderson. We are seeking participants to complete a survey for a research project. The research involves answering some questions about your experience of Chronic Fatigue Syndrome, the way you think about it and the types of support you have around you. The research should take about 30 minutes of your time. Your contribution would be greatly appreciated. To receive more information please click the link, otherwise feel free to ignore this invitation. Thank you for your participation.
Deborah Brooks BA (Hons) and Dr Alistair Anderson PhD MBA GradDip AppSc
Tuesday, September 30, 2014
who wishes to reprint this blog post may do so. (Remember to link back
to the original and provide attribution."
Aside: I posted Jennie Spotila's review of the draft yesterday but it
never came through on my e-mail account. It's here:
Monday, September 29, 2014
The AHRQ Draft Report - Fundamentally and irredeemably flawed
The Jury, by John Morgan
The Agency for Healthcare Quality and Research (AHRQ) has released its
draft report on the Diagnosis and Treatment of Myalgic
Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS).
For those who find it hard to keep track of the plethora of reports,
committees, panels, and reviews currently underway, the AHRQ report
provides the basis for the Pathways to Prevention, or P2P Workshop.
The P2P Workshop has been convened by the NIH for the purpose of
making a report that will be used to evaluate research grants for
ME/CFS, and upon which pharmaceutical companies will base their
The P2P panel is composed entirely of non-experts. The preference for
non-experts was intended, according to Susan Maier, Executive
Secretary for the NIH Advisory Committee on Research on Women's
Health, to act like a "jury," by which she meant the composition of
the panel was meant to be unbiased.
Leaving aside for a moment the absurdity of consigning a research case definition for a disease to people who aren't even physicians, the
jury system itself does not work. Trial by jury is one of the most
inefficient systems of justice in the world. Swayed by bombastic
arguments, prejudice, and crocodile tears, juries of twelve unbiased
peers routinely find innocent people guilty, and allow the guilty to
go free. As a method for determining who gets grants for medical
research, anything even remotely resembling the jury system is
I have touched upon some of the short-comings of the draft report
below. I've tried to keep it brief. (There is so much wrong with this
report that if I were to write a thorough critique, it would be longer
than the report itself.)
You can read the AHRQ draft report and appendices here
You can make comments (until October 20) here
You can read more about the P2P in these posts:
Advocates to NIH - "Pull the P2P!"
All the reasons why the P2P is dangerous
Protocol for Disaster?
Jennie Spotila explains why the AHRQ report is a recipe for disaster,
and how they pulled a "bait and switch" by changing their Key
P2P: The Question They Will Not Ask
Mary Dimmock and Jennie Spotila explain how refusing to consider how
CFS and ME differ will affect the results of the P2P Workshop.
Note: Anyone who wishes to reprint this blog post may do so. (Remember
to link back to the original and provide attribution.)
A BRIEF CRITIQUE OF THE AHRQ DRAFT REPORT
By Erica Verrillo
Point 1: The draft report shows limited understanding of the illness
The report begins with the erroneous statement that "The term ME was
first used in the 1930s after an outbreak of neuromyesthenia ..."
A quick google search would have revealed that "myalgic
encephalomyelitis" was first used in a letter to the editor entitled,
"A New Clinical Entity?" published in the Lancet in 1956. The authors
– Emile Nihoul, Lise Quersin-Thiry, S.Chalmers Parry and Robert A.
Good – were referring to what became known as Royal Free Disease, an
outbreak that occurred in London's Royal Free Hospital in the 1950s.
Obviously, none of the members of the panel felt inclined to check
The report goes on to say that "Uncertainty persists regarding the
etiology and whether the condition reflects a single pathologically
discrete syndrome, subsets of the same illness, or a nonspecific
condition shared by other disease entities." This statement reflects a
thorough misunderstanding of how the illness is perceived by people
who investigate and treat it. There are no experts in ME/CFS who would claim that it is a "nonspecific condition shared by other disease entities." There are, however, numerous researchers who author papers
on "chronic fatigue" and "fatiguing illnesses" such as cancer and MS.
The authors of the AHRQ draft report, unlike experts in the field, do not have enough background to be able to distinguish between "chronic
fatigue" and ME/CFS.
While the introduction to the report is not crucial, it does indicate
that the people writing it not only had no knowledge of the illness,
but that they did not want to spend any time acquiring it. The willful ignorance that is demonstrated in the introduction permeates the entire report.
Point 2: Problematic Search Methods
In order to find abstracts and articles, the AHRQ searched three main
databases using the terms: fatigue; Fatigue Syndrome, Chronic; and
Encephalomyelitis. With the notable exception of PsycINFO, a database
of abstracts of literature in the field of psychology produced by the
American Psychological Association, these are the same databases used
by the Drug Class Review: Drugs for Fibromyalgia: Final Original
published by the Oregon Health & Science University in 2011. Ovid and
EBM/Cochrane are large medical databases, though they don't
necessarily include every study conducted on a given illness or
condition. Only controlled trials are included in the Cochrane
The most glaring problem with the search is that it included studies
on "fatigue." Indeed, a number of studies included in the review were
on "fatiguing illnesses" rather than ME/CFS. Like the introduction,
the search reflects a state of confusion on the part of the authors.
The confusion is not altogether surprising, given that researchers
also appear to be confused about the difference between CFS and
chronic fatigue. Nonetheless, experts in the field are not confused.
They are aware that while ME has been used abroad since the 1950s, it
has not been used as a diagnosis here in U.S. Specialists have been
limited to CFS as a diagnosis, like it or not.
A second problem is that with the perennial lack of NIH funding for
ME/CFS controlled trials, much of the information about treating the
disease is based on clinical observations. None of these were
included. nor were studies that were controlled, but which did not
meet the set of criteria for inclusion in the review – such as
addressing the Key Questions.
Point 3: Studies used for the report are inadequate to address the Key Questions
The studies that the reviewers included were not only too few, they
were completely inadequate to properly address the Key Questions.
The Key Questions to be addressed by the report are as follows:
1. What methods are available to clinicians to diagnose ME/CFS and how
do the use of these methods vary by patient subgroups?
a) What are widely accepted diagnostic methods and what conditions are
required to be ruled out or excluded before assigning a diagnosis of
b) What is the accuracy and concordance of diagnostic methods?
c) What harms are associated with diagnosing ME/CFS?
2. What are the (a) benefits and (b) harms of therapeutic
interventions for patients with ME/CFS and how do they vary by patient
a) What are the characteristics of responders and non-responders to
There are problems with the wording of some of these questions. For
example, in a country in which 80% of the physicians don't believe
that CFS is a real disease, what could "widely accepted" be referring
to? And, "What harms are associated with diagnosing ME/CFS?" seems to
have an a priori assumption that diagnosing the disease may in itself
cause harm. But aside from the oddness of the wording, the studies
they chose do not adequately address the questions.
The criteria for exclusion from the review included, among others,
that the study did not last not long enough (therapeutic trial of less
than 12 weeks), was published before 1988, had wrong study design, or
did not address a Key Question. (There were 8 more exclusions.)
From among the thousands of studies that have been conducted, the
criteria limited the review to a scant 64 studies. Some of the
landmark studies that were excluded were all of the studies
demonstrating immune dysfunction (e.g. NK cell deficiency studies by
Brenu et al.), studies of viral reactivation and antiviral treatments
(e.g. all Lerner and Jessop studies, Kerr parvovirus B19 study),
studies documenting brain abnormalities (e.g. Lange's MRI study), and
all of the papers published by Tom Kindlon on harms associated with
GET and CBT. Not even appearing on the excluded list were the
ground-breaking 2-day CPET studies conducted by Keller, Stevens and
Snell, Peckerman's cardiac insufficiency studies, and the recent
Watanabe study on CNS inflammation.
The fact that some of the most significant studies in the ME/CFS
literature did not even appear on the excluded list was mind-boggling.
Of the studies that appeared on the exclusion list, the reasons given
were various, but among the most frequently cited were that the
studies did not address the Key Questions. Yet, several studies that
directly addressed the Key Questions were omitted (for example, 2-Day
CPET studies were not even considered), while studies that did not
directly address the Key Questions were included. This arbitrariness
permeated the entire study selection process.
(Going though the studies that were accepted I found three that did
not meet the criteria for inclusion without reading further than the
first page. I also found studies in the excluded section that met the
criteria. Having no experience with ME/CFS, the panel lacked the
ability to distinguish relevant from irrelevant studies.)
Point #4: Contradictory and unsupported conclusions
In terms of treatment, the report was heavily weighted toward
psychological studies. Out of the 36 studies used to address Key
Question 2, 14 concerned CBT. Considering that the PACE trial was
included, but not any of its critiques, it is not surprising that the
report favored CBT:
"Based on 13 trials, cognitive and behavioral therapy (CBT), either
group or individual; self-instruction booklets; pragmatic
rehabilitation: peer-to-peer counseling: and symptom consultation
provide improvement in fatigue, function, quality of life, and
employment in adult patients with ME/CFS."
Yet, after a detailed examination of the actual results of the trials,
the report went on to conclude that:
"In summary, head-to-head trials had mixed results with two trials
finding improvement with GET, two trials finding improvement with CBT,
and one trial finding no differences between CBT, GET, and usual care.
In considering non-head-to-head trial data, there is low strength
evidence that CBT and GET provide similar improvement in measures of
fatigue and/or functioning."
Those reading this report will base their recommendations on the first
statement, as the second statement requires wading through a lot of
statistics. They won't even realize that the conclusion that CBT
provides "improvement in fatigue, function, quality, and employment"
is ultimately derived from the results of a single, deeply
manipulated, study. (The PACE trial.)
In terms of Key Question 1, the report suffered from similar
inconsistencies, For example, the report concludes with the statement
that "the negative effects of being given a diagnosis of ME/CFS appear
to be ... universal."
I could not find a single study from among the list of included
studies that would support the conclusion that the diagnosis of ME/CFS
had negative effects universally.
In the Asbring and Narvanen study
<http://www.ncbi.nlm.nih.gov/pubmed/11837367> entitled "Women's
experiences of stigma in relation to chronic fatigue syndrome and
fibromyalgia," the authors concluded that " The women experienced
stigmatization primarily before receiving a diagnosis." [Emphasis
mine] In addition, they stated that "Stigma consisted of questioning
the veracity, morality, and accuracy of patient symptom descriptions
and of psychologizing symptoms."
The Dickson et al. study
"Stigma and the delegitimation experience: An interpretative
phenomenological analysis of people living with chronic fatigue
syndrome," reported that "participants reported delay, negotiation and
debate over diagnosis: further, they perceived their GPs to be
sceptical, disrespectful and to be lacking in knowledge and
interpersonal skills." [Emphasis mine]
In the Green et al. study
"Stigma and Chronic Fatigue Syndrome," the authors state that "Most
subjects (77%) were labeled as 'psychological cases' by one or more of
the physicians (mean = 8) consulted, but of the 4 stigma measures,
only disclosure was related to physician labeling." This means that
patients only felt stigmatized by their physicians after they
attempted to educate them about ME/CFS.
There was nothing in these studies to support the claim that the
diagnosis itself had negative effects. Rather, it was the delay in
diagnosis, and subsequent debate on the part of family and physicians
– as well as the delegitimation resulting from a trivializing name –
that led to negative effects.
The conclusions reached in this review were the result of a poorly
framed set of key questions, a literature search that managed to
exclude the most fundamental research studies, and a misinterpretation
of the studies that were eventually deemed acceptable for inclusion.
As a whole, this report is fundamentally, and irredeemably, flawed -
even given its narrow search results.
These major short-comings are the inevitable result of appointing a group of people who have no expertise in ME/CFS to evaluate 26 years of research. ME/CFS is a disease that demands expertise. It cannot be evaluated be a panel of non-experts.
- See more at: http://cfstreatment.blogspot.ie/2014/09/the-ahrq-draft-report-fundamentally-and.html#sthash.Gh65Hra9.dpuf